This year’s American College of Rheumatology (ACR) meeting, which took place in San Francisco from November 6 to 11, reflected an unprecedented level of innovation, including numerous advances in the area of rheumatoid arthritis (RA).
BioPharma Dive spoke with executives from Pfizer and Eli Lilly to discuss the new treatment landscape and ongoing innovation in this therapeutic space.
Old innovation makes way for new innovation
Twenty years ago, the standard of care for RA was some combination of basic NSAIDS, along with methotrexate. Caregivers focused on symptom relief, and it was widely understood that many patients would fail to achieve remission. Over time, patients would eventually develop severely life-limiting disabilities as their disease progressed.
During this period, researchers presenting at conferences grew excited about data on a new class of drugs known as anti-tumor necrosis factor (TNF) antibodies. In an article published in Acta Orthopaedica Scandinavica in 1995, two physician-researchers wrote the following:
“Primary results have recently been published on the use of anti-TNF monoclonal antibodies. In a controlled trial these antibodies were able to significantly influence a number of disease-activity variables in RA. An important observation was that the clinical effect lasted from weeks to, in some cases, months. Although the potential of these agents for clinical use is still uncertain, these observations suggest that interfering with certain targets of the immune-inflammatory process is possible, effective and so far without side effects.”
About four years after Drs. Van de Putte and Van Riel extolled the virtues of disease-modifying biologics in clinical trials, the first anti-TNF antibody, Remicade (infliximab) was approved in 1999. At that point, the standard of care for RA improved significantly, forever changing the treatment paradigm for patients with RA.
The expanding class of JAK inhibitors
At this year’s ACR meeting, researchers focused on anti-inflammatory antibodies and a relatively new class of oral drugs known as janus kinase (JAK) inhibitors. Interest in JAK inhibitors has spiked since the approval of Pfizer’s oral medication Xeljanz (tofacitinib) —the first, and currently the only,JAK inhibitor approved for the treatment of moderate-to-severe RA.JAK inhibitors have garnered interest because of the role they can play in expanding a treatment area dominated by synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs). Could JAK inhibitors provide the breakthrough in RA that the anti-TNF antibodies provided almost 20 years ago?
Currently, Eli Lilly and Incyte are in late-stage development of baricitinib, a JAK1/JAK2 inhibitor for treatment of RA. Until last December, Johnson & Johnson (J&J) and Astellas were working jointly on another JAK inhibitor, known as ASPO15K, but J&J exercised its opt-out option and left the partnership. Astellas vowed to go it alone or look for a new partner, but there have not been many updates on ASPO15K within the last year.
Innovation means understanding and responding to unmet needs
Like many other therapeutic areas, RA treatments are often used in combination. For some patients, the combination of methotrexate and a powerful biologic, such as Remicade (infliximab), will help a patient achieve remission Yet others will either not respond to methotrexate and Remicade, or will have a negative reaction. Understanding how to help nonresponders achieve relief has become a key area of research in RA.
According to Terence Rooney, MD, Medical Director at Lilly Bio-Medicines,
“A substantial proportion of patients treated with methotrexate – commonly used across the disease continuum for 25 years – do not achieve satisfactory disease control, signaling a need for more effective RA treatment options. In addition, studies have shown that some patients who initially respond to biologics lose response over time, and approximately 40 percent of patients with high disease activity never respond adequately to TNF antagonist biologics.”
Innovative clinical trial design
As Lilly and Incyte approach the end of the development process for baricitinib, they have been collecting results from clinical trials designed to both establish basic efficacy and safety in placebo-controlled and comparator trials, and to obtain data on targeted patient populations.
According to Rooney, “The baricitinib phase three program investigated the benefit of baricitinib across the spectrum of patients with rheumatoid arthritis, including newly diagnosed patients, patients who had failed to respond to conventional DMARDs, and patients who had failed multiple injectable biologic DMARD therapies.”
“In addition, the phase 3 program included two 52-week studies that incorporated either methotrexate or adalimumab as active comparators to provide useful information for therapeutic positioning of baricitinib. In these studies, baricitinib was statistically superior to methotrexate and to adalimumab in improving signs and symptoms, physical function, and important patient-reported outcomes including pain, fatigue and stiffness.”
Rooney also pointed out that there is additional data establishing baricitinib as a DMARD that significantly inhibits progressive radiographic joint damage.
Experience plus evidence equals more innovation
As has become the norm, companies at ACR often highlight new data confirming the efficacy and safety of already approved drugs in larger patient populations and in real-world settings..
Lilly currently has data on more than 40,000 patients worldwide, reflecting its global ambitions. Assuming that baricitinib is approved next year (the goal is to file at the end of the year), Lilly will continue to present data at ACR in the coming years highlighting the results of its long-term extension study, RA-BEYOND.
Pfizer’s up-to-date Xeljanz data presentation at ACR
Although Xeljanz has been on the market for three years in more than 40 countries, Pfizer continues to focus on collecting new data and using it to expand use of Xeljanz. In fact, Pfizer had 20 abstracts focused solely on Xeljanz at ACR 2015.
According to Rory O’Connor, MD, Senior Vice President and Head of Global Medical Affairs, Global Innovative Pharmaceuticals Business, Pfizer, “Ongoing clinical trials and long-term extension studies provide important information about the safety and efficacy of Xeljanz in RA. We are focused on continuing to build on our knowledge of the clinical application of Xeljanz in real-world settings.”
Pfizer was also able to highlight new data that supports their recent NDA for Xeljanz XR, a once-daily formulation of Xeljanz, which is currently approved as a twice-daily dosing formulation.
JAK inhibition beyond RA
One of the most exciting things about the progress with JAK inhibitors is the possibility to innovate treatments beyond RA. Lilly has been exploring the role of JAK-dependent cytokines in the pathogenesis of numerous inflammatory and autoimmune diseases. The company also plans to meet with regulatory authorities to develop a pediatric program for juvenile RA and idiopathic arthritis.
Meanwhile, Pfizer has developed a broad portfolio of various JAK inhibitors and therapies with new modes of action. Already, Pfizer researchers have completed two phase three studies in ulcerative colitis and the top-line results have been positive.
Medical meetings are exciting, because they provide a forum for discussing breakthroughs and portending a future in which the standard of care improves. For companies like Lilly, Incyte, and Pfizer, continual development of more novel approaches to serious diseases is like a call-response echo chamber in which innovation drives more innovation, resulting in better long-term outcomes for patients.